This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our research program integrates functional studies with extensive structural analysis of pattern recognition receptors (PRRs) in complex with their ligands as well as downstream adapters and effector molecules. Both membrane-bound (such as the Toll-like receptors) and cytoplasmic (such as the CATERPILLAR family members and RIG-I/MDA5 antiviral proteins) PRRs are targeted. A critical feature of these innate immune receptors is that they distinguish among various classes of pathogen-specific molecules while retaining responsiveness to a large number of related molecules within a given biochemical class. Understanding such "broad" reactivity at the atomic level is one of the primary goals of the program. Ligand binding by the PRRs not only initiates intracellular signaling cascades leading to innate immune responses against infections, but also allows the innate immune system to orchestrate and potentiate the activities of the adaptive immune system. Our research aims to decipher this signaling network by studying structures of macromolecular complexes using x-ray crystallography.